Hyperexcited neuronal voltage-gated sodium channels (VGSCs) play an integral role in seizure activity, a characteristic symptom of epilepsy. Neuronal VGSCs are heterotrimeric transmembrane proteins that allow sodium ions to permeate through the cell membrane in order to rapidly depolarize local electric fields (i.e., action potentials) across cardiac, neuronal, and skeletal-muscular cell membranes. (Lenkowski, P. W. et al. Neuropharmacology, 2007, 52, 1044-1054 and Lenkowski, P. W. et al. Eur. J. Pharm. Sci., 2004, 21, 635-644).
Neuronal VGSCs exist in three distinct states: active, resting, and inactive. They can be blocked therapeutically in a state-dependent way to treat epilepsy. (Yu, F. H. and Catterall, W. A. Genome Biology, 2003, 4, 207, and Brown, M. L. et al. J. Med. Chem. 1999, 42, 1537-1545). Diphenylhydantoin (DPH) also known as phenyloin was a first-generation anti-epileptic drug (AED) developed in 1938, and continues to serve a major role in treating epilepsy. (Scott, D. F. J. Hist. Neurosci., 1992, 1, 111-118). DPH has shown inactivated state-dependent blocking activity (IC50 40 μM) in neuronal VGSCs. (Brown, M. L. et al. J. Med. Chem. 1997, 40, 602-607).
VGSCs are now known to have a much broader role in human health and disease. They are found most prominently in excitable tissues such as brain, heart, and skeletal muscle but have also been found in non-excitable prostate cancer (PCa) epithelial tissue. (Sikes, R. A, et al., Clinical Prostate Cancer. 2003, 2, 181-187; Fraser, S. P., et al., The Prostate, 2000, 44, 61-76; Shao, B., et al., J Med. Chem. 2004, 47, 4277-4285; and Poupaert, J. R., et al., J Med. Chem. 1989, 27, 76-78). Although the exact purpose of VGSC expression in prostate epithelial tissue is unknown, VGSC upregulation has been linked to prostate adenocarcinoma invasiveness and metastatic potential. (Anderson, J. D., et al., Mol. Cancer. Ther. 2003, 2, 1149-1154).
In addition, the role of ion channels in cancer is an emerging field. Recent studies have demonstrated that voltage-gated ion channels could play a role in the onset, proliferation and malignant progression of various types of cancer, such as prostate, colon, and glioma. (Anderson, James D. Mol Cancer Ther. 2003 November; 2(11):1149-54; Laniado, Marc E. Prostate. 2001 Mar. 1; 46(4):262-74; 154 Preussat, Katja Neurosci Lett. 2003 Jul. 31; 346(1-2):33-6; 155. Wang, Xi-Tao 2000) Specifically, the voltage-gated sodium channel has been shown to play a role in cancer cell proliferation, migration, and adhesion. (Smith, P FEBS Lett. 1998, 423, 19-24. However, the signaling pathways involved in cancer progression are yet to be elucidated. (Fiske, Jamie L. Cancer Metastasis Rev. 2006 September; 25(3):493-500)
Thus VGSC's are attractive targets for drug design, and their structure and interactions have been studied in detail. More specifically, VGSCs are heterotrimeric transmembrane are composed of a large pore-forming α-subunit (260 kDa) that participates in cell-cell interactions, and auxiliary β-subunits. (Catterall, William Neuron. 2000 April; 26(1):13-25). The α-subunit is further divided into four homologous domains (I to IV) containing six transmembrane α-helices (S1-S6); the S4 segments serve as voltage sensors which move outward in the form of a sliding helix to initiate activation of the channel (Catterall, W. A, Novartis Foundation Symposium, 2002, 241, 206-225). To date, nine α-subunit isoforms have been cloned along with four auxiliary β-subunit isoforms. (Goldin, A. L. Annu Rev Physiol. 2001; 63:871-94) These nine sodium channel isoforms are classified by their sensitivity to the neurotoxin tetrodotoxin (TTX). There are six TTX-sensitive isoforms: Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7; and three TTX-resistant isoforms: Nav1.5, Nav1.8, and Nav1.9. (Baker M D. Trends Pharmacol. Sci. 2001, 22, 27-31)
Pharmacological modulation of voltage-gate sodium channels has proven clinically beneficial for the treatment of pain, epilepsy, depression, and cardiac arrhythmias. (Baker M D. Trends Pharmacol. Sci. 2001, 22, 27-3). Local anesthetics, antiarrhythmics, and anticonvulsants are known to act at the batrachotoxin (BTX) binding site located in S6 of domains I, III and IV. (Correa, F. M. A, et al., Neurosci. Lett. 1980, 16, 47-53). Compounds known to bind to the BTX site cause persistent inactivation of the VGSC, which has been measured by voltage (patch) clamp assays. (Sikes, R. A, Walls, A M., Brennen, W. N., Anderson, J. D., Choudhury-Mukherjee, I. Schenck, H. A, and Brown, M. L. Therapeutic Approaches Targeting Prostate Cancer Progression Using Novel Voltage-Gated Ion Channel Blockers. Clinical Prostate Cancer. 2003, 2, 181-187.) Fraser, S. P., Grimes, J. A and Djamgos, M. B. A Effects of Voltage-Gated Ion Channel Modulators on Rat Prostatic Cancer Cell Proliferation: Comparison of Strongly and Weakly Metastatic Cell Lines. The Prostate, 2000, 44, 61-76. Shao, B., Victory, S., Ilyin, V. I., Goehring, R. R., Sun, Q., Hogenkamp, D., Hodges, D. O., Islam, K., Sha, D., Zhang, C., Nguyen, P., Robledo, S., Sakellaropoulos, G., and Carter, R. B. Phenoxyphenyl Pyridines as Novel State-Dependent, High-Potency Sodium Channel Inhibitors. J Med. Chem. 2004, 47, 4277-4285. Poupaert, J. R, Vandervorst, D., Guiot, P., Moustafa, M. M. M., and Dumont, P. Structure-Activity Relationships of Phenyloin-like Anticonvulsant Drugs. J Med. Chem. 1989, 27, 76-78. Anderson, J. D., Hansen, T. P., Lenkowski, P. W., Walls, A M., Choudhury, I. M., Schenck, R A, Friehling, M., Holl, G. M., Patel, M. K., Sikes, R A, and Brown, M. L. Voltage-Gated Sodium Channel Blockers as Cytostatic Inhibitors of the Androgen-Independent Prostate Cancer Cell Line PC-3. Mol. Cancer. Ther. 2003, 2, 1149-1154).
However to date the efficacy of drugs in blocking VGSCs has not exceeded the level attained with DPH 70 years ago. Moreover it has been difficult to assess the activity of AEDs and VGSC-targeting drugs in general following administration. Thus it is an objective of this invention to provide compounds with improved efficacy for blocking targeted VGSC states, and with improved capacity for assessment of activity. However to date the efficacy of drugs in blocking VGSCs has not exceeded the level attained with DPH 70 years ago. Moreover it has been difficult to assess the activity of AEDs and VGSC-targeting drugs in general following administration. Thus it is an objective of this invention to provide compounds with improved efficacy for blocking targeted VGSC states, and with improved capacity for assessment of activity.